The present invention relates to novel cephem compounds, a process for preparing the same, intermediates therefor, and pharmaceutical compositions containing the compounds.
Compounds having an optionally substituted pyridiniomethyl group at the 3-position of the cephem ring have been disclosed in patent applications such as Japanese Patent Publication (KOKAI) 60-237090 (WO 8505106, EP 160969A2), Japanese Patent Publication (KOKOKU) 1-44190 and also Japanese Patent Publication (KOKOKU) 6-70068 (EP 64740B1, U.S. Pat. No. 5,071,979), Japanese Patent Publication (KOKOKU) 2-44476 (EP 159011B1, U.S. Pat. No. 4,833,242), etc. However, there have not been reported compounds wherein a pyridinium ring is substituted with a heterocyclic group having a substituent of the formula xe2x80x94CONHCN or its analogues.
Although a huge number of antibiotics have been marketed so far, the development and characterization of compounds with higher antibiotic activity have been continuously demanded so as to cope with the appearance of multiple drug resistant bacteria and to provide for the diversification of therapy forms. In particular, it has been demanded to develop cephem compounds of broad spectrum which show a long blood half-life and have an excellent in vivo dynamics such as transfer to a tissue.
The present inventors have intensively studied with a purpose for developing novel cephem compounds with superior characteristics and found that cephem compounds wherein the cephem ring has a pyridiniomethyl group at the 3-position, and wherein the pyridinium ring is substituted with a heterocyclic group having a substituent xe2x80x94CONHCN or an analogue thereof have an excellent in vivo dynamics properties.
Thus, the present invention provides a cephem compound wherein the cephem ring has a substituent at the 3-position, which substituent is shown by the formula II: 
wherein
Het is a mono- or polycyclic heterocyclic group comprising one or more hetero atoms selected from the group consisting of N, O and S which may be the same or different from each other; R1 is hydrogen, an optionally substituted lower alkyl or an optionally substituted lower alkenyl; A is an. optionally substituted lower alkylene, an optionally substituted lower alkenylene or a single bond; B is an optionally substituted imino or a single bond; and D is a single bond or a group of the formula: 
xe2x80x83or a salt or a hydrate thereof. The above-mentioned cephem compounds, salts or hydrates may be hereinafter referred to as the compound of the present invention.
The compound of the present invention is preferably represented by the formula I: 
wherein Acyl is an acyl, and Het, R1, A, B and D are as defined above, or an ester, a salt, or a hydrate thereof.
Acyl in the formula I is preferably a group of the formula III: 
wherein X is CH or N; Y is an optionally protected amino; and Z is an optionally substituted hydrocarbon group.
Het in the formula I or II is preferably a 5- or 6-membered trivalent hetero cyclic group comprising one to four hetero atoms selected from the group consisting of N, O and S which may be the same or different from each other, and, more preferably, a pyrrolyl group of the formula IV: 
Further, A in the formula I or II is preferably a single bond or a vinyl group; B is a single bond; and D is a single bond.
Example of preferable compounds of the formula I include those wherein Acyl is a group of the formula III: 
(wherein X is CH or N, Y is an optionally protected amino and Z is hydrogen or an optionally substituted hydrocarbon group); Het is a 5- or 6-membered hetero cyclic group comprising one to four hetero, atoms selected from the group consisting of N, O and S which may be the same or different from each other; A is a single bond or a vinyl group; B is a single bond; and D is a single bond, or an ester, a salt, or a hydrate thereof.
Terms herein used are defined below.
Throughout the present specification, the term xe2x80x9ccephem compoundxe2x80x9d refers to a class of compounds having a double bond between the 3- and 4-positions of the cepham ring and named according to the nomenclature shown under the heading xe2x80x9ccephemxe2x80x9d in The Journal of the American Chemical Society, 84, 3400 (1962). The present invention encompasses compounds of the formula I, pharmaceutically acceptable esters, salts, or hydrates thereof (i.e., esters of Compound I, salts of Compound I, salts of an ester of Compound I, or hydrates thereof). The signal xe2x80x9cxe2x88x92xe2x80x9d in xe2x80x94COOxe2x88x92 at the 4-position of a compound of the formula I indicates that a carboxylate anion forms an intramolecular salt by making a pair with the pyridinium cation on the substituent at the 3-position. When the carboxyl group is not ionized, the pyridinium cation can form a salt with an anion or a counter ion on a side-chain. The present invention encompasses all of these embodiments. The xe2x80x9cSxe2x80x9d at the 1-position of the cephem ring may be oxidized.
The term xe2x80x9cmono- or polycyclic heterocyclic groupxe2x80x9d in the definition of xe2x80x9cHetxe2x80x9d includes the both aromatic and non-aromatic mono- or polycyclic heterocyclic groups, which is bound to the adjacent three groups. In the case of a monocyclic heterocyclic group, examples of a preferred aromatic heterocyclic group include 5- to 6-membered cyclic groups such as furan, thiophene, tetrazole, pyrrole, pyrazole, imidazole, oxazole, thiazole, pyridine, oxazine and triazine. Examples of a preferred non-aromatic heterocyclic group include 5- to 7-membered groups such as pyrrolidine, thiazolidine, oxazolidine, imidazolidine, thiazoline, oxazoline, imidazoline, piperidine, piperazine, morpholine, thiomorpholine, oxadiazoline, and dioxane. Among them, a monocyclic heterocyclic group comprising one or two hetero atoms selected from N and S is more preferable, and pyrrole is most preferred.
Preferred examples of polycyclic heterocyclic groups include those wherein benzene ring, pyridine ring, pyrazine ring, pyridazine ring, pyrimidine ring, or the like, is condensed to an above-mentioned monocyclic aromatic heterocyclic group, such as benzothiophene, indole, benzothiazole, benzofuran, and benzimidazole. Those wherein Het is bound to the 4-position of pyridinium ring are preferred.
The term xe2x80x9clower alkylxe2x80x9d in the definition of xe2x80x9cR1xe2x80x9d refers to a straight or branched C1-6 alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like. C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the like, are preferred. The lower alkyl group may be substituted by a substituent(s) selected from, for example, lower alkenyl group (e.g., C2-6 alkenyl group such as vinyl, butenyl, propenyl, etc.); cycloalkyl group (e.g., C3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); aryl group (e.g., C6-10 aryl group such as phenyl, naphthyl, etc., which aryl group may be further substituted by hydroxy, C1-4 alkyl such as methyl or ethyl, or C1-4 alkoxy such as methoxy or ethoxy); aromatic heterocyclic group (eg., 5- or 6-membered aromatic heterocyclic group comprising 1 to 4 hetero atoms selected from N, O, S, and the like, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; bi- or tricyclic aromatic condensed heterocyclic group comprising 1 to 5 hetero atoms selected from N, O, S, and the like, which is formed by condensing one or two 5- or 6-membered aromatic heterocyclic groups comprising 1 to 4 hetero atoms selected from N, O, S, and the like or one or two benzene rings, such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-inzdazolyl, bonzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, .gamma.-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl, indolydinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl); non-aromatic heterocyclic group (e.g., 4- or 6-membered non-aromatic heterocyclic group comprising 1 to 3 hetero atoms selected from N, O, S, and the like, such as oxiranyl, azetidinyl, oxetanyl, thiethanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperadinyl, and the like); amino group; mono- or di-lower alkyl amino group (e.g., mono- or di C1-6 alkylamino group such as methylamino, ethylamino, dimethylamino, and the like); tri-lower alkylammonium group (e.g., tri C1-6 alkylammonium group such as trimethylammonium, triethylammonium, tripropylammonium, and the like); amidino group; acyl group (e.g., C1-6 alkanoyl group such as formyl, acetyl, propionyl, and the like); carbamoyl group; mono- or di-lower alkylcarbamoyl group (e.g., mono- or di C1-6 alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, and the like); sulfamoyl group; mono- or di-lower alkyl sulfamoyl group (e.g., mono- or di C1-6 alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, and the like); carboxyl group; lower alkoxycarbonyl group (e.g., C1-6 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like); hydroxyl group; lower alkoxy group (e.g., C1-6 alkoxy group such as methoxy, ethoxy, and the like); lower alkenyloxy group (e.g., C2-6 alkenyloxy group such as allyloxy, 2-buthenyloxy, and the like); cycloalkyloxy group (e.g., C3-7 cycloalkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and the like); aralkyloxy group (e.g., C7-10 aralkyloxy group such as benzyloxy, phenethyloxy, and the like); aryloxy group (e.g., C6-10 aryloxy group such as phenoxy, naphthyloxy, and the like); mercapto group; lower alkylthio group (e.g., C6-10 alkylthio group such as methylthio, ethylthio, and the like); aralkylthio group (e.g., C7-10 aralkylthio group such as benzylthio, phenethylthio, and the like); arylthio group (e.g., C6-10 arylthio group such as phenylthio, naphthylthio, and the like); sulfo group; cyano group; azide group; nitro group; nitroso group; halogen (e.g., fluorine, chlorine, iodine, and the like). The number of substituent is preferably 1 to 3 and when there are more than one substituents, they may be the same or different from each other.
The term xe2x80x9clower alkenylxe2x80x9d refers to a straight or branched C2-6alkenyl group such as allyl, propenyl, butenyl, pentenyl, and the like, and allyl is preferred. The lower alkenyl group may be substituted by a substituent(s) similar to those mentioned above for lower alkyl group.
The term xe2x80x9clower-alkylenexe2x80x9d in the definition of xe2x80x9cAxe2x80x9d refers to a group derived from the above-mentioned lower alkyl groups, for example, methylene, ethylene, butylene, propylene, pentylene, and the like, and methylene and ethylene are preferred. The lower alkylene group can be substituted by a substituent(s) similar to those mentioned above for lower alkyl group.
The term xe2x80x9clower alkenylenexe2x80x9d refers to a group derived from the above-mentioned lower alkenyl groups, for example, vinylene, butenylene, propenylene, and the like, and vinylene is preferred. The lower alkenylene group can be substituted by a substituent(s) similar to those mentioned above for lower alkyl group.
The xe2x80x9cacyl groupxe2x80x9d represented by Acyl refers to an acyl group known as a substituent for the 6-amino group of penicillin derivatives as well as the 7-amino group of cephem compounds. Examples of such acyl groups include those derived from organic carboxylic acids such as formyl group; alkylcarbonyl group (alkanoyl group), preferably, (C1-C6)alkyl-carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and the like); (C3-C5)alkenoyl group (e.g., acryloyl, chrotonoyl, maleoyl, and the like); (C3-C10)cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, adamantylcarbonyl, and the like); (C5-C6)cycloalkenyl-carbonyl group (e.g., cyclopentenylcarbonyl, cyclopentadienylcarbonyl, cyclohexenylcarbonyl, cyclohexadienylcarbonyl, and the like); arylcarbonyl group (aroyl group), preferably, (C6-C14)aryl-carbonyl group (e.g., benzoyl, 1- or 2-naphthoyl, and the like); aralkyl carbonyl group, preferably, (C7-C19)aralkyl-carbonyl group (e.g., phenylacetyl, phenylpropionyl, xcex1,xcex1,xcex1-triphenylacetyl, 2-phenetylcarbonyl, 1- or 2-naphthylmethylcarbonyl, benzhydrylcarbonyl, and the like); 5- or 6-membered aromatic heterocyclic carbonyl group (e.g., 2- or 3-thenoyl, 2- or 3-furoyl, nicotinoyl, isonicotinoyl, 4- or 5-thiazolylcarbonyl, 1,2,4-thiadiazol-3- or 1,2,4-thiadiazol-5-yl-carbonyl, and the like); 5- or 6-membered aromatic heterocyclic acetyl group (e.g., 2- or 3-thienylacetyl, 2- or 3-furylacetyl, 4-thiazolylacetyl, 1,2,4-thiadiazol-3-yl-acetyl, 1-tetrazolylacetyl, and the like); alkoxycarbonyl group, preferably, (C1-C6)alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, and the like); aryloxycarbonyl group, preferably, (C6-C14)aryloxy-carbonyl group (e.g., phenoxycarbonyl, 1- or 2-naphtoxycarbonyl, and the like); aralkyloxycarbonyl group, preferably, (C7-C19)aralkyloxycarbonyl group (e.g., benzyloxycarbonyl, and the like); aminoalkylcarbonyl group (e.g.,aminoC1-6alkyl-carbonyl group such as glycyl, aranyl, valyl, leucyl, isoleucyl, seryl, threonyl, cysteinyl, cystynyl, methionyl, asparaginyl, glutamyl, lysyl, arginyl, phenylglycyl, phenylalanyl, tyrosyl, histidyl, tryptophanyl, prolyl, 2-aminoethylcarbonyl, 3-aminopropylcarbonyl, and the like); monoalkyl-aminoalkylcarbonyl group (e.g., monoC1-6alkylamino-C1-6alkyl-carbonyl group such as methylaminomethylcarbonyl, 2-ethylaminoethylcarbonyl, and the like); and dialkylaminoalkylcarbonyl group (e.g., diC1-6alkylamino-C1-6alkyl-carbonyl group such as dimethylaminomethylcarbonyl, diethylaminomethylcarbonyl, and the like).
These acyl group may be substituted by one to three substituents selected from amino, nitro, halogen (e.g., fluorine, chlorine, bromine, and the like), hydroxy, oxo, carbamoyl group, (C1-C4)alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, and the like), (C1-C4)alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, and the like), optionally esterified carboxyl group (e.g., (C1-C6)alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like), (C1-C4)alkoxyimino group which is optionally substituted by carboxyl or halogen (e.g., methoxyimino, ethoxyimino, carboxymethoxyimino, 1-carboxy-1-mehylethoxyimino, fluoromethoxyimino, fluoroethoxyimino, and the like), hydraxyimino group, and 4-ethyl-2,3-dioxopiperadinocarbonylamino group.
The heterocyclic group in the 5- or 6-membered aromatic heterocyclic carbonyl group and 5- or 6-membered aromatic heterocyclic acetyl group as defined above refers to an aromatic heterocyclic group comprising one to four hetero atoms selected from the group consisting of optionally oxidized nitrogen atom, oxygen atom, optionally mono- or dioxidized sulfur atom, and the like, and examples other than those set forth above include pyrrole, imidazole, pyrazole, pyrimidine, pyrazine, pyridazine, indole, isothiazole, oxazole, isoxazole, and triazole.
Preferred examples of Acyl include those shown by the formula (III) wherein X is CH or N; Y is an optionally protected amino; and Z is hydrogen or an optionally substituted hydrocarbon group.
Examples of amino-protecting groups in the definition of Y include an appropriate group used in the field of xcex2-lactam- and peptide chemistry. Preferred amino-protecting group includes formyl, chloroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, p-methcxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and trityl.
Examples of a hydrocarbon group in the definition of xe2x80x9cZxe2x80x9d include lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aralkyl, di- or triaryl-methyl and aryl. The lower alkyl group is a straight or branched alkyl group of, preferably, 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. The lower alkenyl group is a straight or branched alkenyl group of, preferably, 2 to 6 carbon atoms, such as allyl, propenyl, butenyl, pentenyl, and the like. The lower alkynyl group is a straight or branched alkynyl group of, preferably, 2 to 6 carbon atoms, such as propynyl, butynyl, pentynyl, and the like. The cycloalkyl group is preferably a cycloalkyl group of 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The aralkyl group is preferably a group of 7 to 10 carbon atoms, such as benzyl, and the like. The di- or triaryl-methyl group is preferably a di- or tri(C6-10aryl)-methyl group, such as benzhydryl, di(p-tolyl)methyl, trityl, tri(p-tolyl)methyl, and the like. The aryl group is a group of 6 to 10 carbon atoms, such as phenyl, and the like.
The hydrocarbon group shown by xe2x80x9cZxe2x80x9d may be substituted by one to three substituents selected from, for example, carboxyl group; C1-6alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like; carbamoyl group; C1-6alkylthio group such as methylthio, ethylthio, and the like; sulfamoyl group; amino group; hydroxy group; cyano group; carbamoyloxy group; and halogen such as fluorine,.chlorine, and the like. Examples of preferred Z include hydrogen, (C1-C3)lower alkyl group and a lower alkyl group substituted by one or 2 substituents selected from halogen and carboxyl group (e.g., fluoromethyl, fluoroethyl, carboxypropyl, etc.)
Ester derivatives of a compound or an intermediate of the present invention are those formed through the esterification of a carboxyl group(s) in the molecule, and are usable as a synthetic intermediate or a non-toxic metabolic ester which is apt to undergo hydrolysis in vivo.
Examples of ester derivatives usable as a synthetic intermediate include optionally substituted C1-6alkyl ester, C2-6alkenyl ester, C3-10cycloalkyl ester, C3-10cycloalkyl-C1-6alkyl ester, optionally substituted C6-10aryl ester, optionally substituted C7-12aralkyl ester, diC6-10aryl-methyl ester, triC6-10aryl-methyl ester, substituted silyl ester, and the like.
Examples of metabolic ester residues include acetoxymethyl group, 1-acetoxyethyl group, 1-acetoxypropyl group, pivaloyloxymethyl group, 1-isopropyloxycarbonyloxyethyl group, 1-cyclohexyloxycarbonyloxyethyl group, phthalidyl group, (2-oxo-5-methyl-1,3-dioxol-4-yl)methyl, and the like.
When the xe2x80x94COOxe2x88x92 group at the 4-position of Compound I is esterified, the ester residue can be, for example, a group of the formula VIII: 
wherein R7 is hydrogen, an alkyl group, a cycloalkyl group or a cycloalkylalkyl group; R8 is hydrogen, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkyloxy group, a cycloalkylalkyl group, an alkenyloxy group, or a phenyl group; a phthalidyl group; (2-oxo-5-methyl-1,3-dioxol-4-yl)methyl group; an alkoxyalkyl group; an alkylthioalkyl group; a tert-butyl group; a 2,2,2-trichloroethyl group; a benzyl group; a p-methoxybenzyl group; a p-nitrobenzyl group; a benzhydryl group; a trityl group; a trimethylsilyl group; or an allyl group.
In the above definition, the alkyl group or the alkyl moiety in cycloalkylalkyl group, alkoxyalkyl group and alkylthioalkyl group can be, for example, a straight or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, 2,2-dimethylpropyl, etc.), and the cycloalkyl group or the cycloalkyl moiety in cycloalkyloxy group or cycloalkylalkyl group can be, for example, a cycloalkyl group of 3 to 7 carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc). Examples of alkoxy group or alkoxy moiety in alkoxyalkyl group include a straight or a b ranched chain alkoxy group of 1 to 10 carbon atom s (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, decyloxy, etc.) Examples of alkenyloxy group include a straight or a branched chain alkenyloxy group of 2 to 7 carbon atoms (e.g., allyloxy, etc.
As a salt of the compound of the present invention, pharmaceutically acceptable salts are preferred, such as those formed with an inorganic base, an organic base, an inorganic acid, an organic acid, a basic or acidic amino. acid, and intra-molecular salts. Examples of preferred salts formed with an inorganic base include alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; alminium salts; and ammonium salts. Examples of preferred salts formed with an organic base include those formed with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, procaine, 2-phenylethylbenzylamine, trishydroxymethylaminomethane, polyhydroxyalkylamine, N-methylglucosamine, and the like. Examples of preferred salts formed with an inorganic acid include those formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Examples of preferred salts formed with an organic acid include those formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Examples of preferred salts formed with basic amino acid include those formed with arginine, lysine, ornithine, histidine, and the like. Examples of preferred salts formed with an acidic amino acid include those formed with aspartic acid, glutamic acid, and the like.
Among the salts, the base-addition salts (i.e., salts with inorganic or organic base, or basic amino acid) are those which can be formed at the 4-carboxyl group of the cephem ring or an acidic group such as carboxyl group, sulfo group, hydroxyl group, or the like, on the side chain, if any. The acid-addition salts (i.e., salts with inorganic or organic acid, or acidic amino acid) means those which can be formed at a basic group such as amino group, monoalkylamino group, dialkylamino group, cycloalkylamino group, arylamino group, aralkylamino group, N-containing heterocyclic group, or the like, of a compound of the present invention, if any. Acid addition salts also include those having a counter ion such as chloride ion, bromide ion, sulfate ion, p-toluenesulfonate ion, methanesulfonate ion, trifluoroacetate ion, or the like, which are formed when an organic or inorganic acid (1 mole) is attached to the site of a compound of the present invention where an intramolecular salt is formed between the 4-carboxylate moiety,(COOxe2x88x92) and the pyridinium cation on the 3-side chain.
The hydrate of the present invention refers to a mono- or dihydrate. They are obtainable by selecting an appropriate drying method.
The compound of the present invention can be prepared according to a known method in the field of xcex2-lactam. The typical processes are provided below.
[Production Method 1]
A compound of the formula I, or an ester or a salt thereof can be prepared by reacting a cephem compound of the formula V: 
wherein R4 is a carboxy-protecting group, R5 is a hydroxy group, an acyloxy group, a carbamoyloxy group, a substituted carbamoyloxy group, or a halogen atom, or a salt thereof with a pyridine derivative of the formula VI: 
wherein R1, A, B and D are as defined above, or a salt thereof, and optionally deprotecting the reaction product.
In the reaction, Compound V or its salt (hereinafter, they may be referred to as Compound V) and a pyridine derivative VI or its salt (hereinafter, they may be referred to as Compound VI) are reacted to give Compound I through the nucleophilic substitution reaction. Compound V can be easily obtained in accordance with a known method such as those described in Japanese Patent Publication (KOKAI) 231684/1985 or Japanese Patent Publication (KOKAI) 149682/1987, or a method equivalent thereto. Compound VI can be prepared in a manner shown in the working examples below.
The nucleophilic substitution of Compound V by Compound VI is normally carried out in a solvent. Solvents useable in the reaction are ethers (dioxane, tetrahydrofuran, diethylether, etc.), esters (ethyl formate, ethyl acetate, n-butyl acetate, etc.), halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.), hydrocarbons (n-hexane, benzene, toluene, etc.), amides (formamide, N,N-dimethylformamide, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, propionitrile, etc.), and also dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, and water, which are used alone or in combination as a mixed solvent. Further, alcohols such as methanol, ethanol, n-propanol, isopropanol, ethylene glycol, 2-methoxyethanol, can be used.
When Compound VI is liquid, it can be used in a large excess (e.g., 10 to 200-fold moles) to Compound V so that it can serve as a solvent. In such a case, Compound VI can be used in combination with any one or more solvents above to give a mixed solvent.
When R5 in Compound V is an acyloxy group, a carbamoyloxy group or a substituted carbamoyloxy group, more preferred solvent is water, or a mixed solvent of water and a water-miscible organic solvent. Preferred examples of the organic solvent include acetone, methyl ethyl ketone, acetonitrile, and the like. The amount of Compound VI is normally between about 1 to 5 moles, preferably about 1 to 3 moles, based on 1 mole of Compound V. The reaction is conducted at temperature range of about 10 to 100xc2x0 C., preferably about 30 to 80xc2x0 C. The reaction time depends on the kinds of Compound V, compound VI, or the solvent, reaction temperature, or the like, but is normally from about tens minutes to several hours, preferably from about 1 to 5 hours. The reaction is advantageously conducted at the pH range of 2 to 8, preferably about neutral, i.e. pH 5 to 8. This reaction easily proceeds in the presence of 2 to 30 equivalents of iodides or thiocyanates. Examples of such salts include sodium iodide, potassium iodide, sodium thiocyanate, potassium thiocyanate, and the like. The reaction can be allowed to proceed smoothly by adding quaternary ammonium salts having a surface activity action such as trimethylbenzylammonium bromide, triethylbenzylammonium bromide, triethylbenzylammonium hydroxide, and the like, in addition to the above salts.
When R5 in Compound V is a hydroxyl group, the reaction can be effected in the presence of an organophosphorous compound according to the method described, for example, in Japanese Patent Publication (KOKAI) 58-43979 (corresponding to U.S. Pat. Nos. 4,642,365 and 4,801,703).
Preferred solvents usable in the reaction include, for example, the above-mentioned ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitrites and sulfoxides, which are used alone or in combination. Particularly, dichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide, a mixed solvent of dimethylformamide and acetonitrile, and a mixed solvent of dichloromethane and acetonitrile would lead to good results. The amount of Compound VI or a salt thereof, and that of the organophosphorous compound is preferably from about 1 to 5 moles and about 1 to 10 moles, more preferably from about 1 to 3 moles and about 1 to 6 moles, respectively, based on 1 mole of Compound V. The reaction is conducted at temperature range of about xe2x88x9280 to 50xc2x0 C., preferably about xe2x88x9240 to 40xc2x0 C. The reaction time is normally from about 30 minutes to 48 hours, preferably from about 1 to 24 hours. An organic base can be added in the reaction system. Examples of the organic base include amines such as triethylamine, tri(n-butyl)amine, di(n-butyl)amine, diisobutylamine, dicyclohexylamine, and the like. The amount of the base is preferably about 1 to 5 moles based on 1 mole of Compound V.
When R5 in compound V is a halogen atom (preferably iodine), preferable solvents are the above ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols, water, sulfoxides, and the like. The amount of Compound VI is normally from about 1 to 5 moles, preferably from about 1 to 3 moles, based on 1 mole of Compound V. The reaction is conducted at temperature range of about 0 to 80xc2x0 C., preferably about 20 to 60xc2x0 C. The reaction time is normally from about 30 minutes to 15 hours, preferably from about 1 to 5 hours. The reaction can be facilitated in the presence of a dehydrohalogenating agent. Examples of dehydrohalogenating agent usable in the reaction include deacidifying agents such as inorganic bases (e.g. sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogencarbonate, etc.), tertiary-amines (e.g. triethylamine, tri(n-propyl)amine, tri(n-butyl)amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, etc.) and alkylene oxides (e.g. propylene oxide, epichlorohydrin, etc.), but Compound VI itself can be used as the dehydrohalogenating agent. In this case, Compound VI is used in the amount of 2 moles or more based on 1 mole of Compound V.
[Production Method 2]
A compound wherein Acyl in the formula I is shown by the formula III can also be produced through the etherification by reacting a hydroxyimino derivative of the formula VII; 
wherein the respective symbols are as defined above, an ester, or a salt thereof with a compound of the formula ZOH (wherein Z is as defined above) or a reactive derivative thereof. The reactive derivatives of ZOH are those capable of replacing a hydrogen atom of the hydroxyimino compound VII with Z and include, for example, a compound of the formula ZR6 (wherein R6 is a leaving group such as a halogen atom, a mono-substituted sulfonyloxy group, etc.). Examples of the mono-substituted sulfonyloxy group include C1-6alkylsulfonyloxy group and C6-10arylsulfonyloxy group, such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, and the like.
The hydroxyimino compound VII can be synthesized by the method described herein or those known in the art.
The compound ZOH and reactive derivatives thereof can be easily synthesized by a known method, for example, those described in Japanese Patent Publication (KOKAI) Nos. 60-231684 and 62-149682) or analogues thereof.
When using ZOH, the hydroxyimino compound VII is reacted with a compound ZOH by using an appropriate dehydrating agent to synthesize Compound I. Examples of the dehydrating agent used for this purpose include phoshorous oxychloride, thionyl chloride, dialkyl azodicarboxylate (normally used in combination with phosphine), N,Nxe2x80x2-dicyclohexylcarbodiimide, and the like. Preferred dehydrating agent is diethyl azocarboxylate in combination with triphenylphosphine. The reaction using diethyl azocarboxylate in combination with triphenylphosphine is normally conducted in an anhydrous solvent. For example, the above-mentioned ethers and hydrocarbons are used. The compound ZOH, ethyl azodicarboxylate and triphenylphosphine are used in the amount of about 1 to 1.5 moles based on 1 mole of the hydroxyimino compound VII. The reaction takes about several tens minutes to a few hours at temperature range of about 0 to 50xc2x0 C.
When using ZR6, the reaction between ZR6 and the hydroxyimino compound VII is a normal etherification reaction which is conducted in a solvent. As the solvent, there can be used the above-mentioned solvents such as ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitrites, alcohols, water, or the like, or a mixed solvent. The solvent is preferably a mixed solvent of water and a water-miscible solvent, for example, water-containing methanol, water-containing ethanol, water-containing acetone, water-containing dimethyl sulfoxide, or the like. The reaction is also allowed to proceed smoothly in the presence of an appropriate base. Examples of the base include inorganic base such as alkaline metal salts including sodium carbonate, sodium bicarbonate, potassium carbonate, etc., and alkaline metal hydroxides including sodium hydroxide, potassium hydroxide, etc. This reaction can also be conducted in a buffer (e.g. phosphate buffer) at pH 7.5 to 8.5. The compound ZR6 and the base are used at about 1 to 5 moles and about 1 to 10 moles, preferably about 1 to 3 moles and about 1 to 5 moles, respectively, on the basis of 1 mole of compound VII. The reaction temperature can be in the range of about xe2x88x9230 to 100xc2x0 C., preferably about 0 to 80xc2x0 C. The reaction time is about 10 minutes to 15 hours, preferably about 30 minutes to 5 hours.
A function group(s) such as amino, hydroxy, carboxy, or the like, can be protected with an appropriate protecting group when effecting the aforementioned respective reaction.
The method of deprotection and purification for producing the compound of the present invention will be hereinafter explained.
Deprotection Method
For example, a monohalogenoacetyl group (e.g. chloroacetyl, bromoacetyl) can be removed by using thiourea; an alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl) can be removed by using an acid (e.g. hydrochloric acid); an aralkyloxycarbonyl group (e.g. benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl) can be removed by catalytic reduction; 2,2,2-trichloroethoxycarbonyl can be removed by using zinc and an acid (e.g. acetic acid); 2-methylsulfonylethyl ester can be removed by using an alkali; an aralkyl ester (e.g. benzyl ester, p-methoxybenzyl ester, p-nitrobenzyl ester) can be removed by using an acid (e.g. formic acid, trifluoroacetic acid, AlCl3, TiCl4) or by catalytic reduction; a 2,2,2-trichloroethyl ester can be removed by using zinc and an acid (e.g. acetic acid); and a silyl ester (e.g. trimethylsilyl ester, tert-butyldimethylsilyl ester) can be removed by using water alone.
Purification Method
The compound of the present invention or a synthetic intermediate thereof obtained by the above-mentioned or other production methods can be isolated and purified according to known methods including extraction, column chromatography, precipitation, recrystallization, and the like. Further, the isolated compound can then be converted into desired physiologically acceptable salts by a known method.
The compound of the present invention is useful as a drug, especially, a valuable antibiotic because it shows an antibacterial activity of broad spectrum, a long blood half-life, and an excellent in vivo dynamics. Therefore, the compound can be used directly or indirectly for the purpose of preventing or treating various diseases caused by pathogenic microorganisms in human and mammals (e.g. mouse, rat, rabbit, canine, cat, bovine, swine), for example, sinopulmonary infection and urinary infection. The antibacterial spectra are characteristic in the following points.
(1) It is highly active on various Gram-negative bacteria.
(2) It is highly active on Gram-positive bacteria.
(3) It is highly active on methicillia resistant staphylococcus aurous (MRSA).
(4) It is highly active on Pseudomonas which is insensitive to the treatment with a normal cephalosporin antibiotic.
(5) It is also highly active on various Gram-negative bacteria capable of producing xcex2-lactamase (e.g. genus Escherichia, genus Enterobacter, genus Serratia, genus Proteus, etc.).
Microorganisms of the genus Pseudomonas have so far been treated with aminoglycoside antibiotics such as amikacin, gentamicin, and the like. The compound of the present invention has a great advantage over the aminoglycosides because the former exerts antibacterial activities equivalent to the latter with by far the less toxicity to human and animals.
The compound of the present invention can be orally or parenterally administered in the form of solid preparations (e.g. tablets, capsules, granules, powders, etc.) or liquid preparations (e.g. syrups, injections, etc.) in association with pharmaceutically acceptable carriers.
As the pharmaceutically acceptable carriers, there can be used various organic or inorganic carriers which have been commonly used as materials for pharmaceutical preparations. In case of the solid preparation, excipients, lubricants, binders and disintegrators, and in case of the liquid preparation, solvents, solubilizers, suspending agents, isotonicities, buffering agents and soothing agents, can be appropriately combined. If necessary, preparation additives such as antiseptics, antioxidants, colorants and sweetening agents can also be used according to conventional methods. Preferred examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica, and the like. Preferred examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, and the like. Preferred examples of the disintegrator include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium cross carboxymethyl cellulose, sodium carboxymethyl starch, and the like. Preferred examples of the solvent include distilled water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and the like. Preferred examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate., and the like; and hydrophilic polymer such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like. Preferred examples of the isotonicity include sodium chloride, glycerin, D-mannitol, and the like. Preferred examples of the buffering agent include buffer solutions of phosphate, acetate, carbonate and citrate. Preferred examples of the soothing agent include benzyl alcohol, and the like. Preferred examples of the antiseptic include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Preferred examples of the antioxidant include sulfite, ascorbate, and the like. It is also possible to obtain a preparation having an antibacterial activity of broader spectrum by mixing other active ingredient(s) (e.g. xcex2-lactam antibiotic).
The compound of the present invention can be used for preventing and treating bacterial infections such as respiratory infection, urinary infection, pyogenic disease, biliary infection, intestinal infection, obstetric infection, otolaryngologic infection and surgical infection of human and other mammals. Although the dosage varies depending on the conditions and weight of patients and administration method, the daily dose of an active ingredient for adult for parenteral administration can generally be about 0.5-80 mg/kg, preferably about 2-40 mg/kg, which is administered in one to three divisions, by intravenous or intramuscular injection. For oral administration, the daily dose of an active ingredient can be 1-100 mg/kg, preferably about 2.5-50 mg/kg, which is administered in one to three divisions.